The erbB or EGFR family is a subclass of cell surface receptors with intrinsic tyrosine kinase activity known as receptor tyrosine kinases (RTKs). The EGFR family comprises four members: EGFR (also known as erbB1) itself, erbB2 (HER2/Neu), erbB3 and erbB4. EGFR plays a critical role in normal embryonic development and is also known to drive the growth of tumors.
As for most RTKs the first step in the activation of EGFR is ligand induced receptor dimerization. The intracellular kinase domains in the ligand-induced EGFR dimer become activated by autophosphorylation in trans. Subsequent phosphorylation on tyrosines in the regulatory C-terminal tail creates binding sites for the recruitment of multiple downstream signaling molecules via interactions with their SH2 domains.
Abberrant EGFR activation, resulting in EGFR overexpression (known as upregulation) or overactivity is strongly implicated in a cancers, including anal, breast, ovarian, head and neck, lung, pancreatic, and colorectal cancers and glioblastoma multiforme, and is already the target of several anti-cancer therapeutics. Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.
The identification of EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR. Two major strategies have been used for suppressing aberrant EGFR signalling: antibody targeting of the receptor ectodomain and small molecule inhibition of the tyrosine kinase domain. The antibody approach provides high target specificity, but has limitations and challenges in drug development because of the protein nature of the therapeutic agent, including cost and delivery. Cetuximab and panitumumab are examples of monoclonal antibody inhibitors. Other monoclonals in clinical development are zalutumumab, nimotuzumab, and matuzumab. The monoclonal antibodies block the extracellular ligand binding domain. With the binding site blocked, signal molecules can no longer attach there and activate the tyrosine kinase.
Another method of inhibiting abberant EGFR signalling is to use small molecules to inhibit the EGFR tyrosine kinase, which is on the cytoplasmic side of the receptor. Without kinase activity, EGFR is unable to activate itself, which is a prerequisite for binding of downstream adaptor proteins. Ostensibly by halting the signaling cascade in cells that rely on this pathway for growth, tumor proliferation and migration is diminished. Gefitinib, erlotinib, and lapatinib (mixed EGFR and ERBB2 inhibitor) are examples of small molecule kinase inhibitors which function as competitive TKIs by reversibly binding to the ATP site on the EGFR kinase domain. See e.g., Lynch, et al., “Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib,” N. Engl. J Med., 350: 2129-39 (2004); Paez, et al., “EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy,” Science, 304: 1497-1500 (2004), each of which is incorporated by reference in its entirety.

The advantages of small-molecule drugs over therapeutic proteins include the ease of manufacturing and administration, the potential for oral dosing, low immunogenity and applicability to a wider range of disease targets, including those inside the cell. Indeed, small molecule inhibitors of the tyrosine kinase domain of EGFR (i.e., Iressa® and Tarceva®) have been successfully developed as drugs, which directly target the EGFR. But not all patients can benefit from such drugs. Patients can be been divided into EGFR positive and negative, based upon whether a tissue test shows a mutation. One of the most common mutation that sensitizes tumors to small molecule tyrosine kinase inhibitors is the so-called L858R mutation, wherein Leu-858 in the EGFR peptide sequence is replaced by an Arg-858 (so-called “L858R mutation”). EGFR positive patients have shown an impressive 60% response rate which exceeds the response rate for conventional chemotherapy. For example, see Jackman D M, et al., “Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials”. Clin. Cancer Res. 15 (16): 5267-73 (August 2009). However, this mutation which allows for this success exists in only in a small sub-population (ca. 5%) of non-small cell lung cancer patients that harbor this particular mutation in the tyrosine kinase domain of EGFR. Minna, et al., “Cancer. A bull's eye for targeting lung cancer therapy,” Science, 304: 1458-61 (2004), which is incorporated by reference herein in its entirety.
In the metastatic setting, EGFR mutations are strong predictors of efficacy for the EGFR tyrosine kinase inhibitors (TKIs), erlotinib (Tarceva®) and gefitinib (Iressa®). Patients whose tumors harbor EGFR L858R mutations display a >70% radiographic response rate in prospective trials, including randomized phase III trials. Compared to those with EGFR wild-type tumors, patients with EGFR mutant tumors display a longer progression-free survival on EGFR TKI therapy than those who receive chemotherapy. Patients with metastatic EGFR mutant tumors treated with ‘first-generation’ EGFR TKIs have a median survival of more than two years. Prolonged survival may also be due to the fact that patients with EGFR mutant tumors have a better prognosis in general compared to those with EGFR wild-type tumors. Patients with EGFR mutant tumors treated with an EGFR TKI in the first-line setting may live longer than those treated in the second-line setting (30.5 months vs. 23.6 months, p=0.31).
There is a need for small molecule pharmaceuticals which regulate the overexpression of EGFR so as to inhibit cell proliferative disorders characterized by over-activity and/or inappropriate activity of EGFR in a wider population of patients suffering from such disorders, including EGFR-related cancers.